Project Summary/Abstract A clear relationship between amyloid precursor protein (APP), amyloid beta (A?), and mitochondria exists. APP and A? influence mitochondrial function, while mitochondrial function and bioenergetic pathways influence APP processing. Several studies indicate reductions in mitochondrial respiratory flux decrease A? production. Conversely, parameters which increase mitochondrial respiratory flux increase A? production. The overall goal of this study is to determine how bioenergetics influence APP processing pathways. Our preliminary data support a role for mitochondrial membrane potential and reactive oxygen species (ROS) in modulating the production of A?. Based on these findings, we hypothesize mitochondrial membrane potential and mitochondrial derived ROS influence APP processing. We will elucidate the involvement of these bioenergetic intermediates in APP processing pathways and determine how these changes occur. We hypothesize bioenergetics influence APP processing pathways by modulating the cellular localization and trafficking of APP, ?-, and ?-secretases. To this end our proposed studies will explore fundamental relationships between mitochondria, energy metabolism-related phenomena, and A? production. These studies could potentially advance our understanding of Alzheimer?s disease (AD)-associated cascades while also providing translational and relevant insight. Understanding the relationship between A? production and bioenergetics will provide additional clues to the nexus between brain aging and AD, and novel therapeutic targets. This K99/R00 award is designed to further Dr. Wilkins? career path by complimenting her current training and developing expertise in new areas. These new areas include reprogramming induced pluripotent stem cells (iPSCs), ?-, and ?-secretase biology. At the University of Kansas Medical Center (KUMC), Dr. Wilkins will work in the neurology department, where the director of the Alzheimer?s Disease Center (Dr. Russell Swerdlow) is her primary mentor. To facilitate training in new techniques Dr. Wilkins will be assisted by a group of co-mentors. The co-mentors for this award include: Dr. Kenneth Peterson (KUMC) who will provide expertise on Crispr/Cas9 systems and reprogramming iPSCs; Dr. Robert Vassar (Northwestern University) who will provide expertise on ?-secretase biology and manipulations, and Dr. Michael Wolfe (Harvard) who will provide expertise on ?-secretase biology and manipulations. Collaborators will assist with measuring APP processing (Dr. Bruce Yankner, Harvard) and biostatistical analysis (Dr. Jon Mankhen, KUMC). Dr. Wilkins? expert mentoring team and collaborators, strong training environment, and prior research experience are imperative for advancing her career goals.